1. Field of the Invention
The invention relates generally to ocular therapy and, more specifically to methods of treating and preventing photoreceptor degradation by supplying specific subpopulations of the retina with a therapeutic protein, preferably human neurotrophin 4 (NT4), using a recombinant delivery vehicle to target and express the neurotrophic growth factor.
2. Background Information
Retinitis pigmentosa (RP) is a term that refers to group of hereditary disorders that affect the retina's ability to respond to light. While in most cases the disease appears to be autosomal recessive, it may also be autosomal dominant or, infrequently, X linked, and may occur as a part of a syndrome complex. Patients with RP have night blindness in adolescence followed by complete loss of vision in adulthood.
RP primarily affects rod cells, the photoreceptor cell that is responsible for night vision, seeing in dim light, and peripheral vision. Cone cells, which are responsible for color vision and seeing in bright light, may also be affected as the disease progresses.
Rhodopsin is a photosensitive eye pigment found exclusively in rods of the eye. In individuals with the autosomal dominant form of RP, the rhodopsin gene comprises a single nucleotide change. The mutant gene underlies abnormal light-evoked responses from the retina in otherwise presymptomatic individuals and eventually leads to progressive degeneration of both rod and cone photoreceptor cells. The precise mechanism of degeneration is unknown, but may result from the gradual accumulation of undegraded mutant rhodopsin and abnormal membranous discs in the rod cells, with secondary responses of the retina to this malformation.
Neurotrophins are known to play key roles in the survival and differentiation of select neurons in the peripheral and central nervous system (e.g., nerve growth factor (NGF); brain-derived neurotrophic factor (BDNF); and neurotrophin-4 (NT4)). These factors have been shown to act on cells belonging to the visual system. Receptors for these factors are expressed in the retina. Some of these factors may be transported in an anterograde fashion along RGC axons, which together comprise the optic nerve.
In many CNS regions, developing neurons and their connections are overproduced and then partially eliminated. In normal rodents, ˜65% of developing RGCs die by pyknosis. Immature periphery sensory and sympathetic neurons survive by competing for target derived neurotrophins. While the survival-promoting effects of neurotrophins on developing CNS neurons is controversial, neurotrophins have been shown to promote survival of these neurons in vitro, and have been shown to slow or reduce axotomy-induced death of CNS neurons, including developing and mature RGCs.
Accordingly, previous studies have shown that growth factors can rescue dying photoreceptor cells. For example, eight different factors when injected into the retina of rats exposed to constant high intensity light, all showed the ability to delay the degeneration of photoreceptor cells. These include FGF (both acidic and basic forms), BDNF, ciliary neurotrophic factor (CNTF), and interleukin 1 (IL-1). Neurotrophin 3 (NT-3), insulin like growth factor II (IGF-II), transforming growth factor beta (TGF-β) and the tumor necrosis factors alpha and beta (TNF-α, TNF-β) also showed survival activity, but to a much lesser degree than the other factors. However, direct injection of these protein factors is insufficient for long term treatment and maintenance of photoreceptor function.
Recent work has shown that the retinal degeneration phenotype of the rd mouse, which has served as a model for the study of RP for over 30 years, may be rescued by the expression of bovine cGMP phosphodiesterase β-subunit in transgenic mice. Similarly, the retinal degeneration slow (rds) phenotype of the rds mouse may also be corrected by the creation of transgenic mice expressing the wild-type rds gene product, a 39 kDa membrane associated glycoprotein. However, transgenic techniques are not directly applicable to human therapy.
Therefore, there remains a need for sustained in vivo and in situ delivery of neurotrophins in therapies for treating various ocular conditions.